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Dose addition predicts the effects of a mixture of five phthalate esters to inhibit fetal testosterone production and gene expression, and postnatal reproductive development in the Sprague Dawley rat
Citation:
HOWDESHELL, K., V. S. WILSON, J. R. FURR, C. R. LAMBRIGHT, C. V. RIDER, D. Bermudez, AND L. E. GRAY. Dose addition predicts the effects of a mixture of five phthalate esters to inhibit fetal testosterone production and gene expression, and postnatal reproductive development in the Sprague Dawley rat. Presented at 2009 SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
To present at the 2009 SOT Annual Meeting
Description:
Exposure to some phthalate esters (PE) during sexual differentiation induces reproductive malformations in male and female rats. In the fetal male, these lesions result from phthalate-induced reductions in testicular testosterone (T) production and insulin-like hormone 3 (insl3) levels. We hypothesized that dose addition modelling would predict the effects of co-administration of five PEs [benzyl butyl (BBP), di(n)butyl (DBP), diethylhexyl (DEHP), diisobutyl (DiBP) and dipentyl (DPP)] on fetal testicular T production and gene expression since they act via a common mode of toxicity. First, we characterized the dose response effects of six individual PEs on gestation day (GD) 18 testicular T production following exposure to rats on GD8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50=441 mg/kg), and DPP was about 3-fold more potent (ED50=130.9 mg/kg); diethyl phthalate (DEP) had no effect. Next, dams were dosed at 100, 80, 60, 40, 20, 10, 5 or 0% of a mixture of BBP, DBP, DEHP, DiBP (300 mg/kg per chemical) and 100 mg DPP/kg; this ratio was selected so that each phthalate would contribute equally to the reduction in T. As predicted, the PE mixture dose-additively inhibited fetal T production [ED50, observed (obs)=480 vs predicted (pre)=360 mg/kg] and mRNA expression of insl3 (ED50, obs=388 vs pre=288 mg/kg) and steroidogenic genes [cyp11a (ED50, obs=345 vs pre=533 mg/kg) and StAR (ED50, obs=297 vs pre=724 mg/kg)]. In a postnatal study, dose additive effects were observed for the PE mixture on anogenital distance (ED50, obs=743 vs pre=724 mg/kg) as well as other reproductive tract endpoints. The ED50 for female malformations was 450 mg PE mixture/kg. The data demonstrate that individual PEs with a similar mechanism of action elicit dose additive effects on rat reproductive development. This abstract does not necessarily reflect USEPA policy.